This grant proposes to investigate the mechanisms by which ticks modulate host immunity during feeding and how the hosts can acquire increased resistance over repeated infections, resulting in decreased tick fitness. The PI and colleagues have identified an immunosuppressant protein, P36, which is produced in the salivary glands of the tick and secreted into the host wound site. Evidence supports this protein as having immunomodulatory properties. The long-term goal of this research is to understand the cellular and molecular bases by which ticks modulate host immune and to use tick derived immunomodulatory proteins as immunogens in a novel anti-tick vaccine. Specific aims of this grant are: 1) express p36, using a baculovirus expression system, and determine the extent to which both the native and recombinant p36 proteins reduce Con A stimulated lymphocyte proliferation and modulate T-lymphocyte and macrophage cytokine levels in vitro. 2) Determine if immunization with p36 induces an immune response that impairs tick feeding. 3) Examine the temporal expression of p36 mRNA and protein throughout the life cycle and feeding cycle of D. andersoni and determine if p36 is present in the salivary glands of other medically important ixodid ticks. And 4) purify and clone additional immunomodulatory proteins from two size ranges previously identified using preparative SDS-PAGE fractionation, as well as determine their immunomodulatory activities and utility as vaccine immunogens.